SUMMARY Peripheral neuropathy is one of the most debilitating diseases that significantly impacts patient's quality of life with recurring pain and imposes staggering economic burdens to our society. Neuropathic pain also represents a critical unmet medical need because it tends to respond poorly to traditional analgesics and the most commonly used pain medicines produce serious side effects. Therefore, it is important to identify cells, molecules, and neural circuits specifically involved at different stages of the pathogenesis of neuropathic pain to help develop mechanism-based therapies. Transient receptor potential (TRP) channels are a group of ion channels serving as cellular sensors expressed by many cell types. TRPV4 is a polymodal sensory transducer integrating a variety of thermal, mechanical and chemical stimuli. Based on pilot studies, we hypothesize that TRPV4 is required for inflammatory responses that dynamically catalyze neuropathic pain in the spinal cord. To determine the cellular mechanisms underlying TRPV4-mediated neuropathic pain we will use a multidisciplinary approach combining generation of cell- specific TRPV4 mutant mice and bone marrow chimeras, optogenetic activation of TRPV4-expressing cells in the spinal cord, and neuropathic pain behavioral testing. We will also determine if pharmacological inhibition of TRPV4 channels and optogenetic inhibition of TRPV4-expressing spinal cells ameliorate peripheral nerve injury-induced neuropathic pain. This proposal will establish the cellular basis of TRPV4-dependent immune activation during neuropathic pain and explore the potential for pharmacological modulation of neuro-inflammation via inhibition of TRPV4 function. Thus, this study advances a unique opportunity to identify unique molecular and cellular targets for rational design of treatment for neuro-inflammatory diseases resulting in neuropathic pain.